tbuckley/cabot-search huggingface dataset:
A survey on the detection of HPD-related genes by liquid biopsy in patients with lung cancer in China.
Authors: Peng Zhang, Bo Peng, Zhang Jing, Shaochen Cheng
Journal: Journal of Clinical Oncology (2023)

e20502 Background: he prognosis for lung cancer patients receiving immunotherapy is impacted by hyper-progression disease (HPD). Assays for HPD-associated gene mutations were anticipated to be crucial for immunotherapy. Although easy and non-invasive, the liquid biopsy technique is not widely employed in immunotherapy. Here, we want to study details of HPD-related gene mutations in the detection of tissue and liquid biopsy and dig out some relevant information from Chinese Lung Cancer (CLC) patients. Methods: 10 genes with HPD-associated mutation were collected by literature, like SNV ( EGFR, KEAP1, STK11, DNMT3A, PTEN), CNV ( ALK fusion, amplification of MDM2, MDM4, FGF3, FGF4). 3540 cell-free DNA (cfDNA) samples and 6553 tumor tissue samples of LC patients download from Haplab database (HaploX, Shenzhen, China). Genetic alterations were sequenced by NGS platform and microsatellite instability status was calculated through msisensor analysis. The chi-square test was used for statistical hypothesis test. Results: In general, all mutation genes tested except EGFR were detected significantly differently between tissue and cfDNA samples (p &lt; 0.05). 193 samples (156 tDNA, 37cfDNA) with microsatellite instability (MSI) were screened to test HPD-related gene consistency. Results showed no significant difference in 10 HPD-related genes between MSI tissue and blood samples (p &gt; 0.05). Microsatellite stable (MSS) samples of 4499 tumor DNA and 1173 cfDNA were also performed on consistency test. EGFR and the other 4 genes ( FGF3, FGF4, KEAP1, PTEN) were found consistency in tDNA and cfDNA, and ALK (p 0.0051), MDM2 (p 0.0004), MDM4 (p 0.0052), STK11 (p 0.0344), DNMT3A (p &lt; 0.0001) showed significant difference of two type of samples. Conclusions: In overall samples and subtypes tested, only EGFR had no significant differences between tissue and cfDNA, which might make EGFR a perfect biomarker candidate in HPD detection and prognosis. Our outcomes also proved that liquid biopsy has some limitations in monitoring HPD-related genes of CLC compared with tissue biopsy. MSS patients presented more reliable results than MSI patients. When monitoring HPD-related genes except for EGFR using cfDNA, appropriate patients should be considered.
Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline <i>BRCA1</i> or <i>BRCA2</i> (g<i>BRCA</i>1/2+) pathogenic variants: SWOG S2001.
Authors: Vincent Chung, Katherine A Guthrie, Michael J Pishvaian, Kim Anna Reiss, Andrew M. Lowy, Davendra Sohal, Sarah Colby, Elad Sharon, Carmen Joseph Allegra, Eileen Mary O'Reilly, E. Gabriela Chiorean, Philip Agop Philip
Journal: Journal of Clinical Oncology (2023)

TPS4198 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Several clinical studies in solid tumors have shown preliminary efficacy with the combination of PARP plus immune checkpoint inhibitors. Based upon these data, SWOG S2001 aims to further improve the PFS of gBRCA1/2+ mPDA pts. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in December 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 pathogenic variants identified with standard of care germline genetic testing and progression-free after receiving at least 16 weeks of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to compare PFS in mPDA pts treated with olaparib + pembrolizumab versus olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha=0.10, this design requires enrolling 88 pts for a total of 78 eligible and evaluable pts. As of February 2023, 26 participants have been accrued. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Clinical trial information: NCT04548752 .
Mechanism-based peripheral blood biomarkers to evaluate anticancer effects of the plinabulin/docetaxel combination (plin/doc) vs. doc alone in second/third line EGFR wild-type (WT) NSCLC.
Authors: Trevor Feinstein, Y. June Lu, Stephen Duprez, Lore Bai, Lan Huang, Ramon W. Mohanlal
Journal: Journal of Clinical Oncology (2023)

e21017 Background: Pretreatment neutrophil to lymphocyte (L) (NLR), platelet to L (PLR), and L to monocyte (LMR) levels are established prognostic biomarkers for advanced NSCLC. Plinabulin (Plin) is a well-tolerated, differentiated tubulin-binding agent being developed for neutropenia prevention as a monotherapy and in combination, and for improving the efficacy of anticancer agents. DUBLIN-3 (NCT02504489) was a randomized, single-blinded (pts only), active-controlled Ph3 study in 2 nd /3 rd line stage IIIB/IV, EGFR WT NSCLC with a measurable lung lesion (RECIST 1.1). Pts (N = 559) were randomized 1:1 to Plin/Doc or Doc (21-day (D) cycle (C)). Doc (75 mg/m 2 ) on D1 and Plin (30 mg/m 2 ) on D1/D8 were given by IV infusion with steroid premedication (8 mg PO BID x 3D). Differential WBCs and platelet counts were collected at baseline (pre-steroid), D1, and D8. We analyzed the posttreatment effects of Plin on NLR, PLR, and LMR. Methods: All evaluable Plin/Doc vs Doc pts were included. NLR/PLR/LMR ratios and their respective change from baseline (cNLR/cPLR/cLMR) were obtained from blood draws taken at predose, C1D8, and/or C2D8. For intra/inter-arm overall survival (OS) stratification, baseline median NLR (3.2), PLR (177), and LMR (3.5) values were selected as thresholds. By examining responders &amp; long-term survivors in both arms, posttreatment NLR/LMR and cNLR/cLMR thresholds were established for C1D8 and C2D8. Finally, PFS/OS benefits were stratified to determine the statistical significances of Plin/Doc vs Doc. Results: In agreement with literature, baseline threshold levels for NLR = 3.2, PLR = 177, LMR = 3.5 were statistically significantly predictive of OS in both the Plin/Doc and Doc arms (p values ranging from 0.05 to 0.0001). Plin prevents Doc-induced neutropenia, and post-Doc neutrophil counts were higher on D8 with Plin/Doc vs Plin (p &lt; 0.001). Despite Doc-induced myelosuppression, Plin/Doc responding pts maintained similar NLR/LMR values as baseline at C1D8 and C2D8. After a single Plin dose at C1D8, lower NLR (cutoff = 3.0; 1.2x median value of all pts) and higher LMR (cutoff = 4.5; median value of all pts) thresholds independently predicted PFS/OS benefits of Plin/Doc vs Doc. Further, a higher cNLR threshold (cutoff = 0.25) at C2D8, best predicted Plin/Doc vs Doc in PFS and OS (p &lt; 0.0001 and p = 0.0035 respectively). Conclusions: Bone marrow suppression remains a common serious risk of classical/non-classical cancer drugs. Under these conditions, the addition of Plin offers rapid protection of GMP lineage cells which can be captured by simple blood cell counts. Incorporation of blood-based biomarkers may help enrich NSCLC pts with better sensitivity to Plin/Doc combination than Doc alone. Clinical trial information: NCT02504489 .
Tumor mutational burden as a predictive biomarker for molecularly matched therapy in two independent pan-cancer cohorts.
Authors: Damian Tobias Rieke, Till de Bortoli, Manuela Benary, Peter Horak, Mario Lamping, Sebastian Stintzing, Inge Tinhofer, Serge Leyvraz, Reinhold Schäfer, Frederick Klauschen, Ulrich Keller, Albrecht Stenzinger, Stefan Froehling, Razelle Kurzrock, Ivan Jelas, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2023)

3066 Background: Personalized cancer therapy based on molecular tumor aberrations has shown efficacy in a subset of tumors. Novel biomarkers are warranted to help extend this benefit to a larger patient population. Tumor mutational burden (TMB) is an established predictive biomarker for immune checkpoint inhibition. Its role for molecularly matched therapy is unknown. Methods: Comprehensive molecular profiling including whole-exome and RNA-sequencing was performed in 104 patients with advanced cancer within the DKTK MASTER program. 55 patients received a systemic therapy excluding immunotherapy. TMB and survival were analyzed in patients receiving molecularly matched therapy (n=34) or non-molecularly matched therapy (n=21) as well as in an independent published cohort of patients receiving molecularly matched (n=68) or non-molecularly matched (n=40) therapy (excluding immunotherapy). TMB and co-occurring driver mutations were analyzed in the DKTK MASTER cohort. Results: The median TMB of 1.68 mutations per megabase (mut/Mb) in the 34 patients receiving molecularly matched therapy was used to stratify patients into TMB-high and -low groups. Median overall survival (OS) and progression-free survival (PFS) were significantly shorter in the TMB-high than in the TMB-low group (OS: 4 months [95% CI, 3.3 to 7.6] versus 19 months [95%CI, 10.0 to not reached] p &lt; 0.001, Hazard Ratio (HR) 4.4 [95%CI, 1.9 to 10.2], p&lt;0.001; PFS 1.8 months [95%CI, 1.1 to 3.6] versus 8.5 months [95% CI, 2.8 to 17.0] p = 0.004, HR 2.9 [95%CI, 1.4 to 6.2], p=0.005). No significant differences were observed in patients receiving non-molecularly informed systemic therapy (OS HR 0.7 [95%CI, 0.2 to 2.6], p=0.635 and PFS HR 1.2 [95%CI, 0.4 to 3.5] p=0.701). In the validation cohort, shorter progression-free survival was also identified in the TMB-high group (median TMB cut-off of 4 mut/Mb; HR 2.2 [95%CI, 1.3 to 3.7] p=0.005) treated with molecularly matched therapy but not with non-molecularly informed therapy (HR 1.1 [95%CI, 0.5 to 2.2] p=0.848). TMB was associated with co-occurring driver mutations (n=104, r = 0.78 [95%CI, 0.68 to 0.85], p&lt;0.001). Conclusions: High TMB was previously established as a positive predictive biomarker associated with efficacy of immune checkpoint inhibitor treatments. Our study reveals high TMB as a negative predictive biomarker associated with low efficacy of molecularly informed systemic therapy, potentially due to co-occurring driver mutations. Thus, TMB is a candidate predictive pan-cancer biomarker for combined precision oncology and immunotherapy programs.
Efficacy of ramucirumab combination chemotherapy as second-line treatment in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction after exposure to checkpoint inhibitors and chemotherapy as first-line therapy within the prospective phase II IKF-S628/AIO-STO-0417 (MOONLIGHT) trial.
Authors: Michael Masetti, Salah-Eddin Al-Batran, Thorsten Oliver Goetze, Peter C. Thuss-Patience, Jorge Riera-Knorrenschild, Eray Goekkurt, Gunnar Folprecht, Thomas Jens Ettrich, Udo Lindig, Kim Barbara Luley, Daniel Pink, Tobias Nicolaas Dechow, Disorn Sookthai, Sabine Junge, Claudia Pauligk, Sylvie Lorenzen
Journal: Journal of Clinical Oncology (2023)

4043 Background: FOLFOX plus nivolumab has become standard of care for first-line therapy of patients (pts) with advanced gastroesophageal cancer (aGEC). The efficacy of 2 nd line VEGF-2 inhibition with ramucirumab (Ram) plus chemotherapy after progression to immunochemotherapy remains unclear. Methods: Medical records of consecutive pts with aGEC enrolled in the multi-centre randomized phase II AIO-STO-0417 trial who had tumor progression after 1 st line FOLFOX plus nivolumab and ipilimumab were retrospectively analysed. Pts were divided into two groups based on the subsequent 2 nd line therapy: Ram plus chemotherapy (ramucirumab group) or chemotherapy alone (control group). Outcomes were compared between both groups in the overall population and in subgroup analysis according to best response (CR/PR) under 1 st line therapy and tumor PD-L1 expression. Results: In total, 83 pts (38 Ram group, 45 control group) were included. The most frequent 2 nd line therapy in the Ram group was Ram plus paclitaxel (85%). In the overall population, median progression-free survival (PFS) in the Ram group was longerthan in the control group (4.5 vs. 2.9 months). Responders (CR/PR) to 1 st line immunochemotherapy who received Ram containing 2 nd line therapy (n = 15) showed a clearly prolonged median OS counted from start of 1 st line therapy (28.9 vs. 16.5 months), as well as 2 nd line OS (9.6 vs. 7.5 months), PFS (5.6 vs. 2.9 months) and DCR (53% vs. 29%) compared to the control group (n = 24). PD-L1 CPS ≥ 1 (status known for77% of pts) was 42% and 44% for the Ram and the control group, respectively. Patients with CPS ≥ 1 in the Ram group (n = 16) showed a trend towards better tumor control (ORR 25% vs. 10%, DCR 44% vs. 30%) and improved survival (total OS 11.5 vs. 8.0 months; 2 nd line OS 6.5 vs. 3.9 months; PFS 4.5 vs. 1.6 months) compared to the control group (n = 20). Conclusions: Ramucirumab is effective as 2 nd line treatment after progression on 1 st line FOLFOX plus dual checkpoint inhibition, especially in patients with initial response and positive PD-L1 expression. Sequential angiogenesis inhibition with anti-VEGFR-2 targeting therapy following immunochemotherapy might be a promising option to overcome resistance to immunotherapy, which warrants further investigations in a larger cohort. Clinical trial information: NCT03647969 .
Epidemiologic effectors on the breast tumor microenvironment: Results from the Cancer Prevention Study-II and -3 cohorts.
Authors: Maha AT Elsebaie, Mohamed Amgad, James M. Hodge, Mia M. Gaudet, Lauren R. Teras, Ami N. Shah, Lee A.D. Cooper
Journal: Journal of Clinical Oncology (2023)

10530 Background: Despite breast cancer being the leading cancer among women, we have a poor understanding of the impact of epidemiologic risk factors on its tumor microenvironment (TME). We examined risk factors for TME favorability using a novel aggregate marker: the Histomic Prognostic Score (HiPS). Methods: Data were from whole slide image (WSI) scans of hematoxylin &amp; eosin slides from women in the Cancer Prevention Studies CPS-II and -3, diagnosed with nonmetastatic breast cancer. Diagnoses occurred between enrollment and the last administrative date (1992/1993 to 2011 in CPS-II and 2006–2013 to 2018 in CPS-3). Median year of diagnosis was 2004 in CPS-II and 2014 in CPS-3. Using the WSI, a deep-learning model was trained to extract features and summarize the morphology of the epithelium, stroma, and tumor-infiltrating lymphocytes within the TME. These features, along with demographic, tumor biomarkers, and survival data, were then used to generate the HiPS, a novel measurement of “ prognostic favorability” of TME, ranging from 0 (favorable) to 10 (unfavorable). Multivariable linear models estimated associations between the HiPS score and epidemiologic risk factors: hormone replacement therapy use (HRT; current vs. former/never), cigarette smoking (current vs. former/never), alcohol intake (&gt;1 drink vs. &lt;1 drink/day), aspirin intake (daily vs. not daily) controlled for, age at diagnosis, body mass index (BMI), race, and cancer detection method (screen- vs. self-detected). Results: We included 1264 CPS-II and 651 CPS-3 participants in the analysis. Compared to CPS-II, CPS-3 participants were younger (mean (± sd) age 54.7 ± 7.6 vs. 72.2 ± 7, p&lt;0.001), heavier (mean (± sd) BMI 27.1 ± 5.8 vs. 26 ± 4.8, p&lt;0.001), and more diverse (7.4% vs. 2.1% non-White, p&lt;0.001). Most breast cancers (69.9% of CPS-II and 64.1% of CPS-3) were screen-detected, p=0.206. Increasing age and BMI were associated with higher HiPS score in both cohorts, Table. Daily aspirin use and current HRT use were associated with lower HiPS scores in CPS-3 only. The inverse association for HRT use was lost in the following subgroups age &lt; 50, ER-, HER2+, TNM stage-1, and screen-detected cancers. Conclusions: Increasing age and BMI have independent adverse effects on breast TME. Daily aspirin intake and current HRT use were only associated with a favorable TME in the younger, more contemporary cohort. Additional studies are needed to confirm these findings and better understand the role of these epidemiologic factors on the TME. [Table: see text]
Analysis of patients at the Memphis VA Medical Center with positive FIT testing and incomplete GI evaluation during the COVID-19 pandemic.
Authors: Mark Mitchell, Richard Huynh, Lindsey Lands, Alva B Weir
Journal: Journal of Clinical Oncology (2023)

e15542 Background: In 2020, colorectal cancer was the second leading cause of cancer death in the United States 1 . In March 2020, the COVID pandemic began which led to widespread disparities in health care, such as surveillance colonoscopies 2 . A Veterans Health Administration large data review revealed completion rates of colonoscopy for high risk individuals, including positive fecal immunochemical test (FIT) to be unchanged pre-pandemic and during the pandemic at 27% vs 26.5% 3 . Another study reports a non-VA population completion rate within 360 days pre-COVID compared to COVID was 53.9% vs 44% 4 . This research sought to analyze data through a retrospective chart review from the Memphis VA Medical Center, the timing of screening colonoscopies after a positive FIT and reasons for delay in obtaining these. Thereby, evaluating effectiveness in completing the procedures and change effected by the COVID pandemic. Methods: A retrospective cohort study designed to detect rates of completed colonoscopy during and before the COVID pandemic after a positive FIT. Records were reviewed of all positive FIT from 2 specified time frames at the Memphis VA to evaluate completion of colonoscopy after a positive FIT. The charts of 157 VA patients with positive FIT during the pandemic were compared to the charts of 115 VA patients with positive FIT pre-pandemic for colonoscopy completion, evaluating both completion rates within 180 days and chart identified reasons for lack of completion. Both community (CITC) and VA procedures for veterans were included. One tailed Fisher’s exact test was applied to calculate the completion rate difference. Results: Overall completion rate of colonoscopy was 46% in the pre-COVID and rose to 56% in the COVID period [p-value &lt; .05 (.0665)]. Percentage of timely completion ( &lt; 180 days) was 26% pre-COVID, compared to 47% during COVID. Percentage of delay ( &gt; 180 days) in pre-Covid was 74%, compared to 53% during COVID. [p-value &lt; .05 (.0004)]. Reasons for delay both pre-COVID and during COVID are listed below. Conclusions: It can be concluded that there is a statistically significant increase in timely colonoscopy completion during the studied COVID period when compared to the pre-COVID period. The total completion rate was higher at our institution than in the literature, likely due to our inclusion of community colonoscopies and our aggressive case management system. A common reason for delay in all groups was delay/lack of referral. This cause for delay should be improved with additional steps in our case management policy. [Table: see text]
Palliative care in hematopoietic stem cell transplant recipients and impact on survival: A nationwide analysis.
Authors: Naveen Premnath, Adeel Khan, Mohak Pandey, Urvashi Pandey, Fieke W Hoff, Stephen Chung, Praveen Ramakrishnan Geethakumari, Farrukh Tauseef Awan, Larry D. Anderson, Jr, Gurbakhash Kaur, Aimaz Afrough, Heather Wolfe, Elif Yilmaz, Robert Collins, Stephanie Terauchi, Elizabeth Paulk, John W. Sweetenham, Yazan F Madanat
Journal: Journal of Clinical Oncology (2023)

12129 Background: Palliative care benefits have been widely studied in solid tumors with early palliative care demonstrating prolonged survival in several malignancies including lung and esophageal cancer. There are limited data and guidelines for use of palliative care in hematopoietic stem cell transplants (HSCT). Methods: We used the National cancer database (NCDB) to identify HSCT recipients between 2004 to 2017 and retrospectively examined the outcomes based on receipt of palliative care. Chi-square and Wilcoxon tests were used to compare categorical and continuous variables respectively. Kaplan Meier analysis and a Cox multivariable proportional hazards model were used for survival analysis using R software. The NCDB is available as de-identified data. Hence, this study was exempt from a full IRB review. Results: We identified 17,464 eligible patients with hematologic malignancies who underwent HSCT during 2004-2017. The table below shows differences in baseline characteristics in patients who received palliative care vs no palliative care and shows an improved median survival in those receiving vs those not receiving (43.5 vs 31.6 months) (p = 0.0003). Patients with median household income in the lowest quartile as per 2016 survey data were taken as low-income group. A multivariable cox regression analysis that adjusted for age, sex, Charlson-Deyo Comorbidity Index, insurance status, income and Hispanic ethnicity found that integration of palliative care was associated with improved survival outcomes (HR 0.85, CI 0.77- 0.93, p = 0.0002). Conclusions: To our knowledge, this is the largest study demonstrating improved outcomes in HSCT recipients when palliative care was incorporated despite there beingmore economically challenged patients in the group that received palliative care. Although these data are retrospective and correlational, it underscores how palliative care should be incorporated as part of national society guidelines for HSCT recipients. [Table: see text]